Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
  • C07J13/007—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 17 (20)

Definitions

• the invention describes an improved and simplified process for partial particular e-R production of C21-carboxylic acid group in the corresponding steroid carboxylic acids having a A -3-one or ⁇ 1,4 -3-on configuration in the A ring of the steroid skeleton to the corresponding C21 -Alcohol function. If appropriate, further functional groups can also be present in the steroid structure, which remain completely or largely unaffected by this partial reduction.
• Progesterone (4-pregnen-3,20-dione) and in particular progesterone derivatives with an oxygen function in the 11-position (11-oxo, 11 ⁇ -OH, 11 ⁇ -OH) of the formulas (1) to (3 ) are excellent and partly technically used starting materials for the synthesis of precursors of hydrocortisone (cortisol) and finally hydrocortisone itself.
• a reaction scheme for this route can be found, for example, in LF Fieser, M. Fieser "Steroids", pages 737, 738, Verlag Chemie, Weinheim, 1961. Details include the original literature JA Hogg et al, J. Am. Chem. Soc. 77, 4436 (1955), and U.S. Patents 2,683,724 and 2,770,184.
• reaction sequence is shown here somewhat shortened using the example of 11-keto-progesterone (4):
• Dehydroprogesterone and its corresponding derivatives are distinguished by the 3-keto-1,4-diene structure of the A ring, as indicated in the following formulas (Ia) to (3a):
• Difficulties in particular in the series of steroid compounds with 1,4-diene-3-keto structure are the partial reduction of the C21-carboxylic acid grouping to the corresponding C21-alcohol function. The reason for this is the lack of protection of the A ring in compounds of the dehydroprogesterone series.
• the present invention is based on the object of demonstrating a way in which a partial reduction of a C-21 carboxylic acid function in the C17 side chain of steroid compounds is possible, even if there are comparatively sensitive further functional groups in the steroid ring structure.
• further functional groups are in particular the A -3-one structure, the ⁇ 1,4 -3-one structure, further double bonds in the system, in particular in the 17 (20) position and optionally the 9 (11) position, and possible oxygen functions in the 11 position.
• Starting materials are particularly important for all these compounds. which have the ⁇ 1,4 -3-one structure in the A-ring of the steroid skeleton.
• the object of the invention was furthermore to enable a partial or at least largely partial reduction of the carboxyl group function in C 21 without the use of special separate protecting groups for the A-ring structure.
• the invention accordingly relates to a process for the partial reduction of ⁇ 4,17 (2O) - and optionally further double bonds in the 1 (2) and / or 9 (11) position having C 21 steroid carboxylic acids and their esters of the general formula I in which R is hydrogen or a hydrocarbon radical and A is hydrogen, hydroxyl or, together with the carbon atom substituted by A, represents a carbonyl group, and finally, instead of the substituent A, an additional olefinic double bond in the 9 (11) position can also be present, to C 21 Steroid alcohols of the general formula II in which Z has the meaning of A, but here means hydroxyl instead of the carbonyl group.
• the process according to the invention is characterized in that the starting compound of the general formula I which is unprotected in the A ring of the steroid system is reacted with diisobutyl aluminum hydride (D I B A H) in such amounts that the reduction of all O-containing functional groups to the hydroxyl group takes place , whereupon the aluminum-containing reaction intermediate is subjected to the selective Oppenauer oxidation to the 3-keto compound in a manner known per se.
• D I B A H diisobutyl aluminum hydride
• the reduction is carried out without a protecting group for the 1,4-diene-3-keto system of the A ring. Instead, the reducing agent is used in an amount that reduces both the ester group and the 3-keto group. Neither the double bonds of the A ring nor the 17 (20) double bond are attacked.
• the alkoxyaluminum derivative (11), which can be assumed to be an intermediate, is usually not isolated, but, under suitable mild conditions, is directly subjected to selective Oppenauer oxidation by adding an alcohol / ketone mixture (for example isopropanol / acetone).
• an alcohol / ketone mixture for example isopropanol / acetone.
• the 3-keto group is practically exclusively regressed and the C 21 alcohol (10) is obtained in an isolated yield of more than 70%.
• R in the compounds of the general formula I is preferably a hydrocarbon radical with in particular not more than 20 C atoms, advantageously not more than 10 C atoms.
• Aliphatic radicals in particular those with 1-5, preferably 1-3 C atoms, are particularly preferred.
• the most important residue is the methyl residue.
• the partial reduction of the carboxyl or carboxylate group in C 21 according to the invention is also possible in the case of compounds which correspond to the general formula I and contain an additional olefinic double bond in the 9 (11) position.
• A is a hydroxyl group in ⁇ - or ins special in the ß position means. If the starting compounds of the general formula I used according to the invention have a carbonyl group in A - ie A forms a carbonyl group with the C atom substituted by A in the 11-position - then this carbonyl group is also reduced to the corresponding hydroxyl group.
• the 11 ⁇ -hydroxyl group is obtained, which is of particular importance anyway for pharmacological reasons.
• the structure of the A-ring emerges unchanged from the process after completion of the 2-stage reduction and selective oxidation, this having particular technical significance for compounds with the ⁇ 1,4 -3-one structure in the A-ring.
• the starting materials used according to the invention have a double bond in the side chain, moreover, in the preferred embodiment, have the A1,4-diene structure instead of the simpler A4 system and can also have an oxygen function in the 11-position or a further double bond in 9 (11) position. It was therefore not possible to predict with certainty that the reaction described by Eder would be transferable to the compounds used according to the invention.
• CA 63, 13367 (1965) describes the improvement of the reduction of the compounds of the formula (5) to the diol of the formula (8) by using DIBAH instead of LiAIH 4 .
• DIBAH instead of LiAIH 4 .
• this is a reduction in a 4-en-3-keto system protected by enamine formation - cf. the formulas (6) and (8) presented above.
• the reaction usually takes place in the temperature range from approximately -80 ° C. to + 30 ° C., the range from -30 ° C. to room temperature being preferred.
• the temperature range from - 10 to + 5 ° C is particularly suitable.
• the reaction is preferably carried out in the presence of inert solvents, for example aromatic hydrocarbons such as toluene or benzene, but aliphatic hydrocarbons such as hexane or ethers such as diethyl ether and the like are also suitable.
• the reaction time is usually up to 10 hours and is preferably in the range from 2 to 5 hours.
• the reaction is expediently carried out under protective gas, for example under N 2 .
• the work is done in an anhydrous atmosphere.
• DIBAH inert solvent
• the amount of DIBAH used corresponds at least to the stoichiometrically required amount, preferably a slight excess, for example up to 20%, preferably up to about 10% molar excess is used.
• a slight excess for example up to 20%, preferably up to about 10% molar excess is used.
• each keto group needs one Equivalent share of DIBAH.
• the reaction temperature is usually in the range of about 0 to 40 ° C, but can also go beyond. It is expedient to work below 80 ° C.
• Ketone / alcohol / mixtures are used as oxidizing agents. Suitable hydride acceptors are, for example, acetone, cyclohexanone or fluorenone mixed with isopropanol or tert. Butanol as an alcohol component.
• the reaction time here is usually 2 to 20 hours, preferably 4 to 12 hours. The reaction is also carried out under anhydrous conditions.
• the ketone is usually used in a large excess, for example 5 to 50 times, preferably 10 to 20 times the amount stoichiometrically required in order to balance the reaction in the desired direction move.
• Both novel and known compounds can be produced by the method according to the invention.
• New in the context of the unsaturated alcohols obtained according to the invention according to general formula II are the compounds which have the A '-3-one configuration in the A ring of the steroid skeleton and are unsubstituted in the 11 position or also in the 9 (11) position have another double bond.
• these two new C 21-01 compounds are a further subject of the invention.
• the compounds of general formula II obtained according to the invention are valuable products in steroid chemistry and in particular valuable intermediates in the production of pharmacologically active steroid compounds, in particular the prednisone and / or prednisolone series.
• the use of the compounds of the general formula II obtained according to the invention for this last-mentioned purpose also falls within the scope of the present invention and is therefore a further subject of the technical teaching claimed here.
• the hydroxyl group in C 21 is generally first esterified, in particular acetylated.
• Acetylation is achieved, for example, by reacting the C 21-ol compound with acetic anhydride / pyridine or Acetic anhydride / triethylamine / dimethylaminopyridine.
• new, partly known compounds are again obtained.
• New compounds - and thus a further subject of the present invention - are the acetate of pregna-1,4,17 (20) -trien-3-one-21-ol and the corresponding compound with an additional olefinic double bond in 9 (11) -Position.
• Known acetates of this type are corresponding compounds with the ⁇ 4-3-one configuration and / or an oxygen function in the 11-position.
• the aqueous phase extracted 2 x with a little methylene chloride, the organic phases are separated, washed to neutrality, then together over Na 2 S0 4 g concentrated e-dried and after removal of the drying agent to dryness.
• the residue is chromatographed on silica gel with methylene chloride / ethyl acetate (75:25). 2.04 g (72%) of the product are obtained, which are uniform according to thin-layer chromatogram and 1 H-NMR spectrum.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)

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• 1980
  • 1980-05-16 AT AT0262880A patent/AT373901B/de not_active IP Right Cessation
• 1981
  • 1981-05-04 DE DE19813117562 patent/DE3117562A1/de not_active Withdrawn
  • 1981-05-06 EP EP81103421A patent/EP0040355B1/fr not_active Expired
  • 1981-05-11 JP JP7127681A patent/JPS579798A/ja active Pending
  • 1981-05-12 US US06/262,969 patent/US4370271A/en not_active Expired - Fee Related

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